The potential use of ephedrine in Lambert-Eaton myasthenic syndrome : Clinical and electrophysiological evaluation

J Neurol (2008) 255:1259–1260

DOI 10.1007/s00415-008-0856-0

LETTER TO THE EDITORS

JO

N 2856

years did not uncover an underly-ing cancer. Pyridostigmine par-tially improved the patient for the first 2 years, and then DAP was introduced with efficacy over the following 12 months. After another phase of deterioration, two series of IvIg infusions were useful for 2 months. Then ephedrine sulfate was prescribed at a dose of 200 mg/ d and the improvement was so impressive that we decided to quantify the clinical and electro-physiological (Edx) changes before proceeding with ephedrine.

The patient agreed to come for five consecutive days. Muscle test-ing and Hammersmith motor ability score (HMS) were per-formed after the Edx tests. Edx studies were carried out by record-ing CMAP from the abductor digiti minimi muscle (ADM). After a rest period, negative CMAP amplitude was evoked at rest and immediately after 15 s SET [4]. The clinical and Edx changes were recorded each day with 3 repetitions of the fol-lowing 6 experimental conditions: no treatment, 90 minutes after taking 60 mg pyridostigmine, 25 mg 4-DAP, 100 mg ephedrine, pyridostigmine and DAP, ephe-drine and DAP. The results are shown in Fig.1. The highest HMS score correlates with the highest CMAP amplitude at rest obtained during the association of DAP and ephedrine. After obtaining these positive results, ephedrine (200 mg/ d) and DAP (55 mg/d) were taken continuously. Benefits were ob-served after the patient was re-viewed 1, 3 and 6 months after. A moderate increase in blood pres-sure was observed.

Ephedrine is a sympathomi-metic drug with highly active adrenergic effects on the heart and vasculature [1], with untoward effects including hypertension and tachyphylaxis [9]. The precise mechanism of action in the muscle is only partially known. Anin vitro

Carlo Cereda Thierry Kuntzer

The potential use of

ephedrine in

Lambert-Eaton myasthenic

syndrome

Clinical and electrophysiological

evaluation

Received: 6 March 2007 Received in revised form:

12 December 2007 Accepted: 18 December 2007 Published online: 13 June 2008

Sirs: A Cochrane review on treatment of Lambert-Eaton myasthenic syndrome (LEMS) underscores the efficacy of 3,4-diaminopyridine (DAP) and of infusions of immunoglobulins (IvIg) [5]. The addition of pyrido-stigmine may enhance effects of DAP. Ephedrine, a controversial drug used in the past to treat myasthenia gravis without proven benefit [8], has recently been used to improve patients with synaptic congenital myasthenic syndrome [2]. Prompted by these observa-tions, we evaluated the efficacy of ephedrine in one patient with idiopathic LEMS.

We describe a 60 year-old female who developed progressive proximal limb muscle weakness and generalized areflexia. A 300 % potentiation of the compound muscle action potential (CMAP) was demonstrated after a short exercise test (SET) and antibodies against the voltage gated Ca2+

channel were positive. Diagnostic works-up over the following 5

Edx study has shown that ephe-drine increases quantal release of acetylcholine (Ach) [10], and may cause an open-channel blockade of the Ach receptors [6], which cannot fully explain its beneficial effect. In a study using a rat model of myas-thenia, the ephedrine effects were considered unrelated to neuromus-cular transmission but to suscepti-bility to arousal [7]. In the reported Edx trial of ephedrine in synaptic congenital myasthenic syndrome it was concluded that ephedrine may exert a beneficial effect on muscle function at a remote level as a central effect [3]. In our patient we observed a relative mismatch between the good clinical benefit (HMS) and surprisingly low CMAP at rest during treatment with ephedrine alone (see Fig.1, day 5), and this probably reflects the cen-tral beneficial effect. Based on this, we can only speculate on a syner-gic, but useful, effect of ephedrine with DAP. As a limiting factor it should be emphasised that (i) we do not know the safe and therapeu-tic optimum dose of ephedrine per kg body weight, and (ii) that pa-tients should be monitored for potential cardiovascular side effects. Further trials are therefore needed to study the efficacy and tolerability of ephedrine in LEMS.

References

1. Andraws R, Chawla P, Brown DL (2005) Cardiovascular effects of ephedra alkaloids: a comprehensive review. Prog Cardiovasc Dis 47:217–225 2. Bestue-Cardiel M, Sáenz de

Cabezón-Alvarez A, Capablo-Liesa JL, et al. (2005) Congenital endplate acetylcho-linesterase deficiency responsive to ephedrine. Neurology 65:144–146 3. Felice KJ, Relva GM (1996) Ephedrine

in the treatment of congenital myas-thenic syndrome. Muscle Nerve 19: 799–800

C. Cereda, MD · T. Kuntzer, MD (,) Nerve-Muscle Unit, Neurology service CHU Vaudois and University of Lausanne 1011 Lausanne, Switzerland

Tel.: +41-21/3141291 Fax: +41-21/3141290

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Kempen GT, et al. (1993) Effect of ephedrine on muscle weakness in a model of myasthenia gravis in rats. Neuropharmacology 32:373–376

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9. Shekelle PG, Hardy ML, Morton SC, et al. (2003). Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA 289:1537–1545 10. Sieb JP, Engel AG (1993) Ephedrine:

effects on neuromuscular trans-mission. Brain Res 623:167–171   
                     
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Fig. 1 A to C shows examples of raw data of two superimposed traces, the smallest corresponding to the CMAPs evoked at rest and the largest those evoked immediately after a 15 s of maximal voluntary exercise test. Data with no treatment or OFF (A); 90 min after taking ephedrine (B), and after taking ephedrine and DAP (C). Note the huge potentiation obtained in B, as well as the synergic effect of the combined treatment with ephedrine and DAP on the CMAP obtained at rest in C. D Diagram showing the relationship between Hammersmith motor score (HMS), and CMAP amplitude. CMAPs obtained at rest (solid lines) and after exercise (dashed lines) were repeated 3 times. Amplitude is expressed as minimal and maximal, and median values, in the following experimental conditions during 5 different days (D): no treatment (OFF), 90 min after taking (i) 60 mg pyridostigmine (Mestinon), (ii) 25 mg 3,4-diaminopyridine (DAP), (iii) 100 mg ephedrine (EPH), (iv) DAP and pyridostigmine (DAP+ Mestinon) and (v) ephedrine and DAP (EPH+DAP). The CMAPs obtained after exercise are quite similar in amplitude. The highest CMAP amplitude at rest was obtained at D6 (5.2 mV, DAP+ EPH), and correlates with the highest HMS score. The lowest CMAP amplitude obtained at rest was seen at D1 (Off), D2 (Mestinon) and D5 (EPH) (1.4 mV; 1.0 mV; 0.7 mV, respectively). Controversially, the HMS score under ephedrine is relatively high at day 5, probably reflecting the central effect of the drug